tbuckley/cabot-search huggingface dataset:
The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus
Authors: Jun Yup Lee, Dylan J Harney, Jonathan D Teo, John B Kwok, Greg T Sutherland, Mark Larance, Anthony S Don
Journal: Molecular Neurodegeneration (2023)

Abstract Background The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases. Methods Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66–104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ANOVA was used to test the effect of major dementia risk alleles in the TMEM106B and APOE genes on the hippocampal proteome and lipidome, adjusting for age, gender, and post-mortem interval. Fibrillar C-terminal TMEM106B fragments were isolated using sarkosyl fractionation and quantified by immunoblotting. Results Forty proteins were associated with age at false discovery rate-corrected P &lt; 0.05, including proteins that regulate cell adhesion, the cytoskeleton, amino acid and lipid metabolism, and ribosomal subunits. TMEM106B, a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. The increase in TMEM106B levels with ageing was specific to carriers of the rs1990622-A allele in the TMEM106B gene that increases risk for frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, and hippocampal sclerosis with ageing. Rs1990622-A was also associated with higher TMEM106B fibril content. Hippocampal lipids were not significantly affected by APOE genotype, however levels of myelin-enriched sulfatides and hexosylceramides were significantly lower, and polyunsaturated phospholipids were higher, in rs1990622-A carriers after controlling for APOE genotype. Conclusions Our study demonstrates that TMEM106B protein abundance is increased with brain ageing in humans, establishes that dementia risk allele rs1990622-A predisposes to TMEM106B fibril formation in the hippocampus, and provides the first evidence that rs1990622-A affects brain lipid homeostasis, particularly myelin lipids. Our data suggests that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism.
Sexual and Gender Minority Invisibility in Cancer Studies: A Call for Effective Recruitment Methods to Address Cancer Disparities
Authors: B.R. Simon Rosser, Ben C.D. Weideman, G. Nic Rider, Aminah Jatoi, Alexandra M. Ecklund, Christopher W. Wheldon, Kristine M.C. Talley, Shalini Kulasingam, M. Kumi Smith, David R. Jacobs, Darryl Mitteldorf, William West, Rhea Alley, Michael W. Ross
Journal: Journal of Clinical Oncology (2023)

#LGBTQ+ people with cancer are invisibilized: A call for #intersectional cancer research (link here) #healthequity
Obesity management for the hepatologist—What to do, how to do it and why?
Authors: Kymberly D. Watt, Sonali Paul, Mohammad Qasim Khan, Mohammad Siddiqui, Jenny Lam, Tayyab S. Diwan, Michael Camilleri
Journal: Hepatology (2023)

Obesity is highly prevalent in hepatology clinics and has a significant impact on chronic liver disease and patient management. Hepatologists and gastroenterologists need to be actively engaged in the management of obesity. This review provides a detailed approach to this challenging comorbidity.
Higher need for polycystic liver disease therapy in female patients: Sex-specific association between liver volume and need for therapy
Authors: Thijs R.M. Barten, Femke Atsma, Adriaan J. van der Meer, Ron Gansevoort, Frederik Nevens, Joost P.H. Drenth, Tom J.G. Gevers
Journal: Hepatology (2023)

Background and Aims: Prognostic tools or biomarkers are urgently needed in polycystic liver disease (PLD) to monitor disease progression and evaluate treatment outcomes. Total liver volume (TLV) is currently used to assess cross-sectional disease severity, and female patients typically have larger livers than males. Therefore, this study explores the sex-specific association between TLV and volume-reducing therapy (VRT). Approach and Results: In this prospective cohort study, we included patients with PLD from European treatment centers. We explored sex-specific differences in the association between baseline TLV and initiation of volume-reducing therapy and determined the cumulative incidence rates of volume-reducing therapy in our cohort. We included 358 patients, of whom 157 (43.9%) received treatment. Treated patients had a higher baseline TLV (median TLV 2.16 vs. 4.34 liter, p &lt; 0.001), were more frequently female (69.7% vs. 89.8%, p &lt; 0.001), and had a higher risk of liver events (HR 4.381, p &lt; 0.001). The cumulative volume-reducing therapy rate at 1 year of follow-up was 21.0% for females compared to 9.1% for males. Baseline TLV was associated with volume-reducing therapy, and there was an interaction with sex (HR females 1.202, p &lt; 0.001; HR males 1.790, p &lt; 0.001; at 1.5 l). Conclusion: Baseline TLV is strongly associated with volume-reducing therapy initiation at follow-up in patients with PLD, with sex-specific differences in this association. Disease staging systems should use TLV to predict the need for future volume-reducing therapy in PLD separately for males and females.
Scirrhous HCC: Another ‘omic thread in the HCC tapestry
Authors: Joseph W. Franses, Dan G. Duda
Journal: Hepatology (2023)

1Section of Hematology-Oncology, Department of Medicine, University of Chicago Comprehensive Cancer Center, Chicago, IL, USA 2Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Commentary on "Hypoxia-driven tumor stromal remodeling and immunosuppressive microenvironment in scirrhous hepatocellular carcinoma" by Chen et al. Correspondence Joseph W. Franses. Email: [email protected]
Reply: NAFLD improves risk prediction of type 2 diabetes—With effect modification by sex and menopausal status
Authors: Yejin Kim, Yoosoo Chang, Seungho Ryu, Sarah H. Wild, Christopher D. Byrne
Journal: Hepatology (2023)

Kim, Yejin; Chang, Yoosoo; Ryu, Seungho; Wild, Sarah H.; Byrne, Christopher D. Author Information
Spatial proximity of tumor-immune interactions predicts patient outcome in hepatocellular carcinoma
Authors: Evan Maestri, Noemi Kedei, Subreen Khatib, Marshonna Forgues, Kris Ylaya, Stephen M. Hewitt, Limin Wang, Jittiporn Chaisaingmongkol, Mathuros Ruchirawat, Lichun Ma, Xin Wei Wang
Journal: Hepatology (2023)

Background and Aims: The fitness and viability of a tumor ecosystem are influenced by the spatial organization of its cells. We aimed to study the structure, architecture, and cell-cell dynamics of the heterogeneous liver cancer tumor microenvironment using spatially resolved multiplexed imaging. Approach and Results: We performed co-detection by indexing multiplexed immunofluorescence imaging on 68 HCC biopsies from Thai patients [(Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC)] as a discovery cohort, and then validated the results in an additional 190 HCC biopsies from Chinese patients [Liver Cancer Institute (LCI)]. We segmented and annotated 117,270 and 465,632 cells from the TIGER-LC and LCI cohorts, respectively. We observed 4 patient groups of TIGER-LC (IC1, IC2, IC3, and IC4) with distinct tumor-immune cellular interaction patterns. In addition, patients from IC2 and IC4 had much better overall survival than those from IC1 and IC3. Noticeably, tumor and CD8 + T-cell interactions were strongly enriched in IC2, the group with the best patient outcomes. The close proximity between the tumor and CD8 + T cells was a strong predictor of patient outcome in both the TIGER-LC and the LCI cohorts. Bulk transcriptomic data from 51 of the 68 HCC cases were used to determine tumor-specific gene expression features of our classified subtypes. Moreover, we observed that the presence of immune spatial neighborhoods in HCC as a measure of overall immune infiltration is linked to better patient prognosis. Conclusions: Highly multiplexed imaging analysis of liver cancer reveals tumor-immune cellular heterogeneity within spatial contexts, such as tumor and CD8 + T-cell interactions, which may predict patient survival.
Letter to the Editor: NAFLD improves risk prediction of type 2 diabetes—With effect modification by sex and menopausal status
Authors: Mubashra Khalid, Zoraiz Munir Khan, Ahmad Sheraz Kahloon
Journal: Hepatology (2023)

1Allama Iqbal Medical College, Lahore 229D, AWT, Phase 2, near Adda Plot, Lahore 2Allama Iqbal Medical College , Lahore, 106-D , Phase 2 , Garden Town , Gujranwala 3Allama Iqbal Medical College , Lahore Article type: Letter to the editor Declaration: None Correspondence Mubashra Khalid, Institute: Allama Iqbal Medical College, Lahore, 229D, AWT, Phase 2, near Adda Plot, Lahore. Email: [email protected]
Which Patients With Rhabdomyosarcoma Need Radiotherapy? Analysis of the Radiotherapy Strategies of the CWS-96 and CWS-2002P Studies and SoTiSaR Registry
Authors: Ewa Koscielniak, Beate Timmermann, Marc Münter, Jadwiga Weclawek-Tompol, Ruth Ladenstein, Felix Niggli, Gustaf Ljungman, Ines B. Brecht, Bernd Blank, Erika Hallmen, Monika Scheer, Joerg Fuchs, Guido Seitz, Claudia Blattmann, Monika Sparber-Sauer, Thomas Klingebiel
Journal: Journal of Clinical Oncology (2023)

To analyze and compare the indications, doses, and application methods of radiotherapy (RT) and their influence on prognosis of patients with localized rhabdomyosarcoma (RMS).One thousand four hundred seventy patients with localized RMS 21 years and younger entered on CWS-96, CWS-2002P, and SoTiSaR were eligible for the analysis. The median follow-up was 6.5 years (IQR, 3.3-9.5).The 5-year event-free survival (EFS) and local control survival (LCS) for 910 (62%) irradiated versus nonirradiated patients were 71% versus 69% and 78% versus 73% (P = .03), respectively. Ninety-five percent of patients in IRS I (90% embryonal RMS [eRMS]) were nonirradiated (EFS, 87%). Irradiated patients with IRS II had improved LCS (91% v 80%; P = .01) and EFS (not significant). In IRS III, EFS and LCS were significantly better for RT patients: 71% versus 56% (P = 3.1e-06) and 76% versus 61% (P = 4.1e-07). Patients with tumors in the head and neck region (orbita, parameningeal, and nonparameningeal) and in other sites had significantly better EFS and LCS and in parameningeal also overall survival (OS). The efficacy of low RT doses of 32 Gy (hyperfractionated, accelerated RT [HART]) and 36 and 41.4 Gy (conventional fractionated RT [CFRT]) in the favorable groups and higher doses of 44.8 Gy (HART) and 50.4 and 55.4 Gy (CFRT) in the unfavorable groups was comparable. Proton RT was used predominantly in head/neck-parameningeal (HN-PM) tumors, with similar EFS and LCS to photon RT.RT can be omitted in patients with IRS I eRMS. RT improves LCS and EFS in IRS II and III. RT improves OS in patients with HN-PM, with proton RT comparable with photon RT. Doses of 32 Gy (HART) or 36 and 41.4 Gy (CFRT) had comparable efficacy in patients with favorable risk profiles and 44.8 Gy (HART) or 50.4 and 55.8 Gy (CFRT) in the unfavorable groups.
Bile acid–induced IRF3 phosphorylation mediates cell death, inflammatory responses, and fibrosis in cholestasis-induced liver and kidney injury via regulation of ZBP1
Authors: Yuan Zhuang, Martí Ortega-Ribera, Prashanth Thevkar Nagesh, Radhika Joshi, Huihui Huang, Yanbo Wang, Adam Zivny, Jeeval Mehta, Samir M. Parikh, Gyongyi Szabo
Journal: Hepatology (2023)

Cell death and inflammation play critical roles in chronic tissue damage caused by cholestatic liver injury leading to fibrosis and cirrhosis. Liver cirrhosis is often associated with kidney damage, which is a severe complication with poor prognosis. Interferon regulatory factor 3 (IRF3) is known to regulate apoptosis and inflammation, but its role in cholestasis remains obscure. In this study.
Hypoxia-driven tumor stromal remodeling and immunosuppressive microenvironment in scirrhous HCC
Authors: Shuling Chen, Changyi Liao, Huanjing Hu, Junbin Liao, Zebin Chen, Shuang Li, Xuezhen Zeng, Bo Peng, Shunli Shen, Dongming Li, Shaoqiang Li, Jiaming Lai, Sui Peng, Yubin Xie, Ming Kuang
Journal: Hepatology (2023)

Background and Aims: Scirrhous HCC (SHCC) is one of the unique subtypes of HCC, characterized by abundant fibrous stroma in the tumor microenvironment. However, the molecular traits of SHCC remain unclear, which is essential to develop specialized therapeutic approaches for SHCC. Approach and Results: We presented an integrative analysis containing single-cell RNA-sequencing, whole-exome sequencing, and bulk RNA-sequencing in SHCC and usual HCC samples from 134 patients to delineate genomic features, transcriptomic profiles, and stromal immune microenvironment of SHCC. Multiplexed immunofluorescence staining, flow cytometry, and functional experiments were performed for validation. Here, we identified SHCC presented with less genomic heterogeneity while possessing a unique transcriptomic profile different from usual HCC. Insulin-like growth factor 2 was significantly upregulated in SHCC tumor cells compared to usual HCC, and could serve as a potential diagnostic biomarker for SHCC. Significant tumor stromal remodeling and hypoxia were observed in SHCC with enrichment of matrix cancer–associated fibroblasts and upregulation of hypoxic pathways. Insulin-like growth factor 2 was identified as a key mediator in shaping the hypoxic stromal microenvironment of SHCC. Under this microenvironment, SHCC exhibited an immunosuppressive niche correlated to enhanced VEGFA signaling activity, where CD4 + T cells and CD8 + T cells were dysfunctional. Furthermore, we found that another hypoxic-related molecule SPP1 from SHCC tumor cells suppressed the function of dendritic cells via the SPP1-CD44 axis, which also probably hindered the activation of T cells. Conclusion: We uncovered the genomic characteristics of SHCC, and revealed a hypoxia-driven tumor stroma remodeling and immunosuppressive microenvironment in SHCC.
RNA nanomedicine in liver diseases
Authors: Anita Bakrania, Yulin Mo, Gang Zheng, Mamatha Bhat
Journal: Hepatology (2023)

The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest. In this review, we discuss in-depth the different types of RNA and nanocarriers used for liver targeting along with their specific applications in metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancers. We further highlight the strategies for cell-specific delivery and future perspectives in this field of research with the emergence of small activating RNA, circular RNA, and RNA base editing approaches.
Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states
Authors: Jackson Nyman, Thomas Denize, Ziad Bakouny, Chris Labaki, Breanna M. Titchen, Kevin Bi, Surya Narayanan Hari, Jacob Rosenthal, Nicita Mehta, Bowen Jiang, Bijaya Sharma, Kristen Felt, Renato Umeton, David A. Braun, Scott Rodig, Toni K. Choueiri, Sabina Signoretti, Eliezer M. Van Allen
Journal: Cell Reports Medicine (2023)

Clear cell renal cell carcinoma (ccRCC) is molecularly heterogeneous, immune infiltrated, and selectively sensitive to immune checkpoint inhibition (ICI). However, the joint tumor-immune states that mediate ICI response remain elusive. We develop spatially aware deep-learning models of tumor and immune features to learn representations of ccRCC tumors using diagnostic whole-slide images (WSIs) in untreated and treated contexts (n = 1,102 patients). We identify patterns of grade heterogeneity in WSIs not achievable through human pathologist analysis, and these graph-based "microheterogeneity" structures associate with PBRM1 loss of function and with patient outcomes. Joint analysis of tumor phenotypes and immune infiltration identifies a subpopulation of highly infiltrated, microheterogeneous tumors responsive to ICI. In paired multiplex immunofluorescence images of ccRCC, microheterogeneity associates with greater PD1 activation in CD8
Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
Authors: Bertrand Allard, Célia Jacoberger-Foissac, Isabelle Cousineau, Yacine Bareche, Laurence Buisseret, Pavel Chrobak, David Allard, Sandra Pommey, Franck Ah-Pine, Sebastien Duquenne, Fabien Picard, John Stagg
Journal: Cell Reports Medicine (2023)

Inhibition of adenosine A2A receptor (A2AR) is a promising approach for cancer immunotherapy currently evaluated in several clinical trials. We here report that anti-obesogenic and anti-inflammatory functions of A2AR, however, significantly restrain hepatocellular carcinoma (HCC) development. Adora2a deletion in mice triggers obesity, non-alcoholic steatohepatitis (NASH), and systemic inflammation, leading to spontaneous HCC and promoting dimethylbenzyl-anthracene (DMBA)- or diethylnitrosamine (DEN)-induced HCC. Conditional Adora2a deletion reveals critical roles of myeloid and hepatocyte-derived A2AR signaling in restraining HCC by limiting hepatic inflammation and steatosis. Remarkably, the impact of A2AR pharmacological blockade on HCC development is dependent on pre-existing NASH. In support of our animal studies, low ADORA2A gene expression in human HCC is associated with cirrhosis, hepatic inflammation, and poor survival. Together, our study uncovers a previously unappreciated tumor-suppressive function for A2AR in the liver and suggests caution in the use of A2AR antagonists in patients with NASH and NASH-associated HCC.
A blood-based metabolomic signature predictive of risk for pancreatic cancer
Authors: Ehsan Irajizad, Ana Kenney, Tiffany Tang, Jody Vykoukal, Ranran Wu, Eunice Murage, Jennifer B. Dennison, Marta Sans, James P. Long, Maureen Loftus, John A. Chabot, Michael D. Kluger, Fay Kastrinos, Lauren Brais, Ana Babic, Kunal Jajoo, Linda S. Lee, Thomas E. Clancy, Kimmie Ng, Andrea Bullock, Jeanine M. Genkinger, Anirban Maitra, Kim-Anh Do, Bin Yu, Brian M. Wolpin, Sam Hanash, Johannes F. Fahrmann
Journal: Cell Reports Medicine (2023)

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of >13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies.
Boosting NAD: An opportunity for metabolic reprogramming of Th17 cells in psoriatic disease
Authors: Eva Reali
Journal: Cell Reports Medicine (2023)

Metabolic reprogramming of CD4 T cells has become an opportunity for adjunctive therapies. Here, Han et al. show that boosting NAD<sup>+</sup> blunts systemic Th17 responses and increases antioxidant pathways through arginine and fumarate-mediated activation of NRF2 transcription factor.
Symptom tracking in endometriosis using digital technologies: Knowns, unknowns, and future prospects
Authors: Katherine Edgley, Andrew W. Horne, Philippa T.K. Saunders, Athanasios Tsanas
Journal: Cell Reports Medicine (2023)

Endometriosis is a common chronic pain condition with no known cure and limited treatment options. Digital technologies, ranging from smartphone apps to wearable sensors, have shown potential toward facilitating chronic pain assessment and management; however, to date, many of these tools have not been specifically deployed or evaluated in patients with endometriosis-associated pain. Informed by previous studies in related chronic pain conditions, we discuss how digital technologies may be used in endometriosis to facilitate objective, continuous, and holistic symptom tracking. We postulate that these pervasive and increasingly affordable technologies present promising opportunities toward developing decision-support tools assisting healthcare professionals and empowering patients with endometriosis to make better-informed choices about symptom management.